Methacrylic anhydride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

26.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA R.8 (2012) and ECETOC (2010)

Overall assessment factor (AF):

13.3

Dose descriptor starting point:

NOAEC

Modified dose descriptor starting point:

NOAEC

Value:

158.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

The initial dose descriptor is the NOAEC of 352 mg MAA /m³ (= 100 ppm MAA) for reduced body weight gain in the presence of reduced feed intake given MAA 6h/d in an OECD 413 study for 90 d. A molecular weight correction factor of 1.117 was used to consider MAA as toxicological relevant moiety which is present two times in MAAH (see chapter "Toxicokinetics"). The resulting NOAEC of 315 mg MAAH /m³ corresponds to 50 ppm MAAH.

The NOAEC for MAAH as starting point was then modified as follows:

- factor 6/8 (Correction of exposure duration to default worker exposure (8 h/d; ECHA R.8, 2012))

- factor6.7 m³/10 m³(Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m³/6.7 m³; ECHA R.8, 2012)

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

The NOAEC is based on a 13-week study. AF 2 for extrapolation from sub-chronic to chronic (ECHA R.8; 2012)

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012).

AF for other interspecies differences:

1

Justification:

Due to the known metabolism of MAAH via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

AF for intraspecies differences:

3

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

The NOAEC is reliable. No adjustment is required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

79.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

4.42

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

78.8 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECHA R.8 (2012) and ECETOC (2010)

Overall assessment factor (AF):

4.47

Dose descriptor:

NOAEC

Value:

236.25 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

1

Justification:

For irritation at the site of contact, progression of the lesion over time is absent or minimal (AF chosen in accordance to ECETOC 2010).

AF for interspecies differences (allometric scaling):

1

Justification:

Due to the known metabolism of MAAH via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences not justified.

AF for other interspecies differences:

1

Justification:

Due to the known metabolism of MAAH via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences not justified.

AF for intraspecies differences:

3

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

The NOAEC is reliable. No adjustment is required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.72 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA R.8 (2012) and ECETOC (2010)

Overall assessment factor (AF):

18.5

Dose descriptor starting point:

NOAEL

Modified dose descriptor starting point:

NOAEL

Value:

161.2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The initial dose descriptor is the NOAEL of 124/164 mg MMA /kg bw/d (= 2000 ppm MMA) for female and male rats in an early 2-year chronic drinking water study – no relevant adverse effects found in MMA as metabolite donor substance. A molecular weight correction factor of 1.3 was used to consider MAA as toxicological relevant moiety which is present two times in MAAH (see chapter "Toxicokinetics"). The resulting NOAEL of 161.2/213.2 mg MAAH /kg bw/d

corresponds to 1000 ppm MAAH.

The NOAEL for MAAH as starting point was then modified as follows:

- factor 1 ( Default factor for oral-to-dermal extrapolation (ECHA R.8, 2012))

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required

AF for differences in duration of exposure:

1

Justification:

The NOAEL is based on an chronic study: no AF required (R.8; 2012)

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to humans (ECHA R.8, Table R.8-3; 2012)

AF for other interspecies differences:

1

Justification:

Due to the known metabolism of MAAH via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences not justified..

AF for intraspecies differences:

3

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of relative high quality, being rated K2. No adjustment is required.

AF for remaining uncertainties:

2

Justification:

The AF of 2 covers the sum of minor uncertainties including a) the hydrolysis rate of MAAH in vivo in comparison to MMA as donor substance of MAA, b) the age of the study; c) the molecular weight correction factor based on the assumption that the methacrylic moiety is the relevant moiety for systemic effects

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20.16 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6.15

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

DNELs derivation for MAAH, CAS 760-93-0

(by ECHA R.8 (2012) and ECETOC (2010))

 

Local effects

Skin irritation

MAAH

Skin irritating Cat 2-> medium hazard forworkers and gen pop.

 

Eye irritation

MAAH

Eye damage Cat 1-> medium hazard forworkers and gen pop.

 

Irritation to the respiratory tract

MAAH

STOT SE 3-> medium hazard forworkers and gen pop.

 

Skin sensitisation

MAAH

Skin sensitising Cat 1 (A) -> high hazard forworkers and gen pop.

 

Systemic effects, short term

Acute toxicity

MAAH is classified for its acute toxicity by oral and inhalation route. The respective DNELs were calculated by applying an AF in the range of 1 to 5 in ECHA’s R.8 document (2012), namely an AF of 3. The respective systemic, short term DNELs are calculated at the end of each table below.

 

Sytemic effects

 

DNEL inhal worker

Description	Value/ factor	Remark
Initial dose descriptor: NOAEC MAA	352 mg MAA /m^3 (100 ppm MAA)	NOAEC for reduced body weight gain in the presence of reduced feed intake given MAA 6h/d in an OECD 413 study for 90 d
Molecular weight correction	1.117	Correction factor for using the results of MAA for MAAH:         2 x molecular weight of MAA (= toxicological relevant moiety) divided by that of MAAH (= 172.18 g/mol ÷154.16 g/mol)
Step 1) Relevant dose descriptor: NOAEC MAAH	315 mg MAAH /m^3 (50 ppm MAAH)
Step 2) Modification of starting point	6/8   6.7 m^3/10 m^3	- Correction of exposure duration to default worker exposure (8 h/d; ECHA R.8, 2012) -Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m^3/6.7 m^3;ECHA R.8, 2012)
Route-to-Route extrapolation	1	Not applicable
NAEC worker	158.29 mg/m^3
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012). Due to the known metabolism of MAAH via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
Intraspecies	3	Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)
Exposure duration	2	The NOAEC is based on a 13-week study. AF 2 for extrapolation from sub-chronic to chronic (ECHA R.8; 2012)
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining uncertainties.
DNELlong-term MAAH
Based upon a NOAEC of 352 mg/m3 for reduced body weight gain in the presence of reduced feed intake given MAA (as primary metabolite) 6h/d in an OECD 413 study for 90 d	26.5 mg MAAH /m^3		Using a total factor (POD modifier and AF) of 13.3 (1.117 x 6/8 x 6.7/10 x 1 x 1 x 3 x 2 x 1 x 1 x 1) a DNELlong-term, systemic, inhal, workerof 26.5 mg/m³ is derived for MAAH.
DNELshort-term
Long-term to short term extrapolation	3		Mean value of range 1 to 5 according to ECHA R.8 (2012)
Based upon a NOAEC of 352 mg/m3 for reduced body weight gain in the presence of reduced feed intake given MAA (as primary metabolite) 6h/d in an OECD 413 study for 90 d	79.5 mg/m^3		Using a total factor (POD modifier and AF) of 4.42 (1.117 x 6/8 x 6.7/10 x 1 x 1 x 3 x 2 x 1 x 1 x 1 x 1/3 ) a DNELshort-term, systemic, inhal, workerof 79.5 mg/m³ is derived for MAAH.

 

DNEL dermal worker long-term

Description	Value/ factor	Remark
Initial dose descriptor: NOAEL MMA	124/164mg[1]MMA /mg bw/d (2000 ppm MMA)	NOAEL for female and male rats in an early 2-year chronic drinking water study – no relevant adverse effects found in MMA as metabolite donor substance (Borzelleca et al. 1964)
Molecular weight correction	1.3	Correction factor for using the results of MAA for MAAH:         2 x molecular weight of MMA (due to MAA toxicological relevant moiety) divided by that of MAAH (= 200.24 g/mol ÷154.16 g/mol)
Step 1) Relevant dose descriptor: NOAEL MAAH	161.2/213.2mg^1MAAH / mg bw/d (1000 ppm MAAH)
Step 2) Modification of starting point	1	Default factor for oral-to-dermal extrapolation (ECHA R.8, 2012)
NAEL worker	161.2/213.2mg^1MAAH / mg bw/d
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans (ECHA R.8, Table R.8-3; 2012)
Intraspecies	3	Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)
Exposure duration	1	The NOAEL is based on an chronic study: no AF required (R.8; 2012)
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of relative high quality, being rated K2. No adjustment is required.
Remaining uncertainties	2	The AF of 2 covers the sum of minor uncertainties including a) the hydrolysis rate of MAAH in vivo in comparison to MMA as donor substance of MAA, b) the age of the study; c) the molecular weight correction factor based on the assumption that the methacrylic moiety is the relevant moiety for systemic effects
DNEL long-term MAAH
Based upon a NOAEL for female and male rats in an early 2-year chronic drinking water study – no relevant adverse effects found at 2000 ppm MMA as metabolite donor substance	6.72 mg^1MAAH /kg bw/d for male workers  (8.88 mg^1MAAH /kg bw/d for female workers)		Using a total factor (POD modifier and AF) of 18.5 (1.3 x 1 x 4 x 3 x 1 x 1 x 1 x 2) a DNELlong-term, systemic, dermal, workerof 6.72 mg/kg bw/d is derived.
DNELshort-term
Long-term to short term extrapolation	3		Mean value of range 1 to 5 according to ECHA R.8 (2012)
Based upon a NOAEL for female and male rats in an early 2-year chronic drinking water study – no relevant adverse effects found at 2000 ppm MMA as metabolite donor substance	20.16mg^1MAAH /kg bw/d for male workers		Using a total factor (POD modifier and AF) of 6.15 (1.3 x 1 x 4 x 3 x 1 x 1 x 1 x 2 x 1/3) a DNELshort-term, systemic, dermal, workerof 20.16 mg/kg bw/d is derived.

 

Local effects

 

DNEL inhal worker

Description	Value/ factor	Remark
Step 1) Initial dose descriptor: NOAEC MAA	352 mg MAA /m^3 (100 ppm MAA)	NOAEC for hypertrophy/ hyperplasia of the respiratory epithelium in the nasal cavity of two female rats given MAA 6h/d in an OECD 413 study for 90 d
Molecular weight correction	1.117	Correction factor for using the results of MAA for MAAH:         2 x molecular weight of MAA (= toxicological relevant moiety) divided by that of MAAH (= 172.18 g/mol ÷154.16 g/mol)
Relevant dose descriptor: NOAEC MAAH	315 mg MAAH /m^3 (50 ppm MAAH)
Step 2) Modification of starting point	6/8	- Correction of exposure duration to default worker exposure (8 h/d; ECHA R.8, 2012) -Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is not required for a local, concentration driven effect (ECHA 2012)
Route-to-Route extrapolation	1	Not applicable
NAEC worker	236.25 mg MAAH /m^3
Step 3) Assessment factors
Interspecies	1	Due to the known metabolism of MAAH via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences not justified.
Intraspecies	3	Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)
Exposure duration	1	For irritation at the site of contact, progression of the lesion over time is absent or minimal (AF chosen in accordance to ECETOC 2010).
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	No remaining uncertainties.
DNELlong-term MAAH
based on NOAEC for local effects in subchronic inhalation study of 352 mg MAA /m3 (100 ppm MAA) = 315 mg MAAH/ m3 (50 ppm MAAH)	78.8 mg MAAH /m^3 (12.5 ppm MAAH)		Using a total factor (POD modifier and AF) of 4.47 (1.117 x 6/8 x 1 x 1 x 3 x 1 x 1 x 1 x 1) a DNELlong-term, local, inhal, workerof 78.8 mg/m³ is derived for MAAH.
DNELshort-term	medium hazard for workers (< STOT SE cat 3 (respiratory system); ECHA Part E, 2016)

[1]for males and females, respectively

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

The substance is used as an intermediate in closed systems only on industrial scale. Therefore the establishment of DNELs for general population is not necessary.